DESCRIPTION (provided by candidate): This proposal describes a five-year training program for the development of an academic career in translational HIV/AIDS research. The principal investigator has completed clinical training in internal medicine and infectious disease, and will now expand upon his clinical and scientific experience through a unique integration of lab-based science and epidemiology training that is designed to establish the PI as an independent researcher. To date, HIV vaccine development has focused primarily on eliciting either cellular or neutralizing antibody responses, an approach that has met with limited success. Thus it is critical that the protective capacity of other adaptive immune mechanisms be examined. Antibody-dependent cellular cytotoxicity (ADCC) has been of increasing interest as a result of recent studies suggesting that there is an association with ADCC and reduced viral replication in HIV-infected humans and SIV-infected macaques. Little is known about this response, particularly in HIV-exposed humans. Mother to infant HIV transmission, particularly in the post-partum, breastfeeding period, provides an opportunity to understand the role of this response in prevention of infection. Antibodies are present in high concentrations in infants at the time of birth and these antibodies have the potential to interact with cytolytic effector cells resulting in killing of HIV-infected cells, such as those present in breastmilk. We hypothesize that a potent ADCC response to autologous maternal viral variants (Aim 1) and a broad ADCC response to heterologous vertically transmitted variants (Aim 2) are associated with protection from infection using archived plasma samples from a breastfeeding study in Nairobi, Kenya. To test this we will construct a panel of full-length envelope variants to generate infectious clones to be used in a novel ADCC assay. These data will allow the comparison of responses in HIV-exposed infants to infants that are infected by breastfeeding. If the ADCC response does indeed correlate with prevention of transmission, this response may be a candidate for targeting with future HIV vaccines. RELEVANCE: HIV/AIDS continues to expand as a global epidemic, and an effective vaccine is desperately needed. What immune response is needed in a vaccine, however, is unknown. The current study aims to examine one part of the immune system, antibody dependent cellular cytotoxicity, to determine if this type of response plays a role in prevention of mother to child HIV transmission. These results may inform future vaccines.